2-Decarboxy-2-aminomethyl-PGI2 compounds

ABSTRACT

The present invention relates to 2-decarboxy-2-aminomethyl-PGI 2  compounds, having pharmacological activity. Particularly, the compounds described herein are useful as platelet aggregation inhibitors.

DESCRIPTION CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of co-pending application Ser. No.819,940, filed July 28, 1977 pending; which is a continuation-in-part ofSer. No. 725,550, filed Sept. 22, 1976, now abandoned; which was acontinuation-in-part of Ser. No. 716,770, filed Aug. 23, 1976, nowabandoned.

BACKGROUND OF THE INVENTION

The present invenion relates to novel compositions of matter which arederivatives of prostacyclin or PGI₂. The chemical name for prostacyclinis (5Z)-5,6-didehydro-9-deoxy-6,9α-epoxy-PGF₁ α. Specifically thepresent invention relates to 2-decarboxy-2-aminomethyl-PGI₂ compounds.

Prostacyclin itself was first reported as "PGX" by Moncada and hisco-workers. See Moncada, et al., Prostaglandins 12:658-713 (1976).Prostacylcin is a circulating hormone in the arterial circulation ofmammals. See "Prostacyclin As A Circulating Hormone, " Nature273:767-768 (29 June 1978) and Grycleweski, R. J., et al., "Generationof Prostacyclin by Lungs in Vivo And Its Release Into ArterialCirculation", Nature 273:765-767 (29 June 1978).

PRIOR ART

Subsequent to any invention described herein the existence ofprostacyclin as a naturally-occurring composition of matter was reportedin the aforementioned references.

SUMMARY OF THE INVENTION

The present invention relates to

a compound of the formula ##STR1## or a mixture comprising that compoundand the enantiomer thereof, wherein W₂ is α--OH:β--H, α--H:β--OH, oxo,methylene, α--H:β--H, or α--CH₂ OH:β--H;

wherein L is

(1) --(CH₂)_(d) --C(R₂)₂ --,

(2) --CH₂ --0--CH₂ --Y--, or

(3) --CH₂ CH═CH--,

wherein d is zero to 5, R₂ hydrogen, methyl, or fluoro, being the sameor different with the proviso that one R₂ is not methyl when the otheris fluoro, and Y is a valence bond, --CH₂ -- or --(CH₂)₂ --,

wherein Q is oxo, α--H:β--H, α--R₈ :β--OH, or α--OH:β--R₈, wherein R₈ ishydrogen or alkyl of one to 4 carbon atoms, inclusive,

wherein R₉ is hydrogen, methyl, or ethyl, and wherein R₁₈ is hydrogen,alkyl of one to 4 carbon atoms, inclusive, aralkyl of 7 to 12 carbonatoms, inclusive, phenyl, or phenyl substituted with alkyl of one to 4carbon atoms, inclusive,

wherein R₄ is

--C(R₅)(R₆)C_(g) H_(2g) --CH₃,

--C(R₅)(R₆)--Z--(Ph I), or

--CH₂ --CH═CH--CH₂ CH₃,

wherein C_(g) H_(2g) is alkylene of one to 9 carbon atoms, inclusive,with one to 5 carbon atoms, inclusive, in the chain between --CR₅ R₆ andterminal methyl, wherein R₅ and R₆ are hydrogen, alkyl of one to 4carbon atoms, inclusive, or fluoro, being the same or different, withthe proviso that one of R₅ and R₆ is fluoro only when the other ishydrogen or fluoro and the further proviso that neither R₅ nor R₆ isfluoro when Z is oxa (--O--); wherein Z represents an oxa atom (--O--)or C_(j) H_(2j) wherein C_(j) H_(2j) is a valence bond or alkylene ofone to 9 carbon atoms, inclusive, with one to 6 carbon atoms, inclusivebetween CR₅ R₆ -- and (Ph I); wherein (Ph I) is phenyl optionallysubstituted by one, 2, or 3 alkyl of one to 4 carbon atoms, inclusive,fluoro, chloro, trifluoromethyl, or --OR₇ -- wherein R₇ is alkyl of oneto 4 carbon atoms, inclusive, with the proviso that not more than twosuch substituents are other than alkyl and such substituents beingeither the same or different; and ps wherein X is p1 (1) trans--CH═CH--,

(2) cis--CH═CH--,

(3) --C.tbd.C--, or

(4) --CH₂ CH₂ --;

including the lower alkanoates thereof.

Compounds in accordance with the present invention are prepared bychemical methods and have pharmacological uses as are described in U.S.Pat. No. 4,158,667, incorporated here by reference. Accordingly,compounds in accordance with the present invention are useful for avariety of pharmacological purposes. Accordingly, the compounds inaccordance with the present invention are especially useful whenever itis desired to inhibit platelet aggregation, to reduce the adhesivecharacter of platelets, and to remove or prevent the formation ofthrombi in mammals, including man. For example, these compounds areuseful in the treatment and prevention of myocardial infarcts, to treatand prevent post-operative thrombosis, to promote patency of vasculardrafts following surgery, and to treat conditions such asatherosclerosis, arteriosclerosis, blood clotting defects due tolipemia, and other clinical conditions in which the underlying etiologyis associated with lipid imbalance or hyperlipidemia. Other in vivoapplications include geriatric patients to prevent cerebral ischemicattacks and long-term prophylaxis following myocardial infarcts andstrokes. For these purposes, the compounds are administeredsystemically, e.g. intravenously, subcutaneously, intramuscularly, andin the form of sterile implants for prolonged action. For rapidresponse, especially in emergency situations, the intravenous route ofadministration is preferred. Dosages in the range about 0.01 to about 10mg/kg of body weight per day are used, the exact dose depending on theage, weight, and condition of the patient or animal, and on thefrequency and route of administration.

The addition of these compounds to whole blood provides in vitroapplications, such as storage of whole blood to be used in heart-lungmachines. Additionally, whole blood containing these compounds can becirculated through limbs and organs, e.g., heart and kidneys, whetherattached to the original body, detached and being preserved or preparedfor transplant, or attached to a new body. Blocking of aggregatedplatelets is avoided by the presence of these compounds. For thispurpose, the compound is added gradually or in single or multipleportions to the circulating blood, to the blood of the donor person oranimal, to the perfused whole body, attached or detached, to therecipient, or to two or all of those at a total steady state dose ofabout 0.001-1.0 μg/ml of whole blood. These compounds are also useful inpreparing platelet-rich concentrates from blood for use in treatingthrombocytopenia or in chemotherapy.

I claim:
 1. A compound of the formula ##STR2## or a mixture comprisingthat compound and the enantiomer thereof, wherein W₂ is α--OH:β--H,α--H:β--OH, oxo, methylene, α--H:β--H, or α--CH₂ OH:β--H;wherein L is(1) --(CH₂)_(d) --C(R₂)₂ --, (2) --CH₂ --0--CH₂ --Y--, or (3) --CH₂CH═CH--,wherein d is zero to 5, R₂ is hydrogen, methyl, or fluoro, beingthe same or different with the proviso that one R₂ is not methyl whenthe other is fluoro, and Y is a valence bond, --CH₂ -- or --(CH₂)₂ --,wherein Q is oxo, α--H:β--H, α--R₈ :β--OH, or α--OH:βR₈, wherein R₈ ishydrogen or alkyl of one to 4 carbon atoms, inclusive, wherein R₉ ishydrogen, methyl, or ethyl, and wherein R₁₈ is hydrogen, alkyl of one to4 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive,phenyl, or phenyl substituted with alkyl of one to 4 carbon atoms,inclusive, wherein R₄ is --C(R₅)(R₆)C_(g) H_(2g) --CH₃,--C(R₅)(R₆)--Z--(Ph I), or --CH₂ --CH═CH--CH₂ CH₃,wherein C_(g) H_(2g)is alkylene of one to 9 carbon atoms, inclusive, with one to 5 carbonatoms, inclusive, in the chain between --CR₅ R₆ and terminal methyl,wherein R₅ and R₆ are hydrogen, alkyl of one to 4 carbon atoms,inclusive, or fluoro, being the same or different, with the proviso thatone of R₅ and R₆ is fluoro only when the other is hydrogen or fluoro andthe further proviso that neither R₅ nor R₆ is fluoro when Z is oxa(--O--); wherein Z represents an oxa atom (--O--) or C_(j) H_(2j)wherein C_(j) H_(2j) is a valence bond or alkylene of one to 9 carbonatoms, inclusive, with one to 6 carbon atoms, inclusive, between CR₅ R₆-- and (Ph I); wherein (Ph I) is phenyl optionally substituted by one,2, or 3 alkyl of one to 4 carbon atoms, inclusive, fluoro, chloro,trifluoromethyl, or --OR₇ -- wherein R₇ is alkyl of one to 4 carbonatoms, inclusive, with the proviso that not more than two suchsubstituents are other than alkyl and such substituents being either thesame or different; and wherein X is (1 ) trans--CH═CH--, (2)cis--CH═CH--, (3) --C.tbd.C--, or (4) --CH₂ CH₂ --;including the loweralkanoates thereof.
 2. A compound according to claim 1, wherein W₂ isα--H:β--OH.
 3. A compound according to claim 1, wherein W₂ is oxo.
 4. Acompound according to claim 1, wherein W₂ is methylene.
 5. A compoundaccording to claim 1, wherein W₂ is α--H:β--H.
 6. A compound accordingto claim 5, wherein L is --(CH₂)_(d) --C(R₂)₂, d being 3, 4, or 5,wherein Q is oxo or α--OH:β--R₈, wherein R₈ is limited to hydrogen,methyl, or ethyl, and wherein R₄ is n-pentyl, 1,1-dimethylpentyl,1,1-difluoropentyl, --CH₂ --O--(Ph) or --C₂ H₄ --(Ph), wherein (Ph) isphenyl.
 7. A compound according to claim 1, wherein W₂ is α--CH₂OH:β--H.
 8. A compound according to claim 1, wherein W₂ is α--OH:β--H.9. A compound according to claim 8, wherein L is --(CH₂)_(d) --C(R₂)₂, dbeing 3, 4, or 5, wherein Q is oxo or α--OH:β--R₈, wherein R₈ ishydrogen, methyl, or ethyl, and wherein R₄ is n-pentyl,1,1-dimethylpentyl, 1,1-difluoropentyl, --CH₂ --O--(Ph) or --C₂ H₄--(Ph), wherein (Ph) is phenyl.
 10. A compound according to claim 8,wherein L is --(CH₂)_(d) --C(R₂)₂, d being 3, 4, or 5, wherein Q is oxoor α--OH:β--R₈, wherein R₈ is hydrogen, methyl, or ethyl, and wherein R₄is cis--CH₂ --CH═CH--CH₂ CH₃.